Summary Iron deficiency caused by regular blood donation is a problem facing blood centers. Each blood donation removes 200 to 250 mg of iron from the donor. Consequently, many donors become iron deficient with repeated donation. This presents a challenge to blood centers that has become more acute in recent years with the realization that iron deficiency even in the absence of anemia is associated with adverse effects including fatigue and decreased exercise tolerance, as well as neurological symptoms such as decreased cognitive function, pica and restless leg syndrome. REDS-II (NHLBI Retrovirus Epidemiology Donor Study-II) is a consortium of 6 blood centers located across the United States. REDS-II investigators performed a longitudinal study investigating the iron status of blood donors over a two year period called the REDS-II Donor Iron Status Evaluation (RISE). Results from the baseline analysis of regular donors (e 2 donations per year (females) or e 3 donations per year (males) revealed that over two-thirds of female donors and over one-half of male donors have iron deficiency. To both safeguard donor health and prevent the loss of committed blood donors, the time has come for blood centers to address this problem of donor iron deficiency. Here we propose to utilize a consortium of three of the REDS-II blood centers to assess potential interventions that will prevent/mitigate iron deficiency in blood donors. Subjects for the proposed studies will be recruited from RISE donors. The availability of these donors whose iron status is well studied for two years in RISE will allow us to assess changes in laboratory data, donation experience and donor symptoms over a combined 4-year period between the two studies. In Specific Aim 1 we will determine if providing donors with accurate information about their iron status and appropriate courses of action, such as prolonging donation intervals or taking iron supplements, will influence them to take independent steps to improve their iron status. In Specific Aim 2 we will provide donors with a 60-day supply of multiple vitamins formulated with 38, 19 or 0 mg of elemental iron to take following each blood donation. The primary outcome for both Specific Aims is to determine how the interventions change donor iron status as assessed by measurement of plasma ferritin, plasma soluble transferrin receptor and reticulocyte hemoglobin content. Secondary outcomes are to determine how the interventions change the proportion of donor visits resulting in successful collection of a unit of blood and how they change the proportion of donor visits resulting in low hematocrit deferral. Tertiary outcomes are to determine how the interventions change the prevalence of donor fatigue, pica and restless leg syndrome as assessed by a survey administered at the beginning and end of the study. Findings from the proposed studies will provide important information on the efficacy of various approaches for iron replacement in blood donors and lay the groundwork for effective programs that can be readily implemented by community blood centers.